PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia and a major public health problem. Data from genetic, biochemical, animal, and human studies suggest that the amyloid-? (A?) peptide plays a key early role in initiating disease pathogenesis and that the microtubule associated protein tau plays a critical role in neurodegeneration and disease progression. Progressive accumulation of A? in the brain appears to ultimately lead to and exacerbate downstream events directly linked to cognitive decline and dementia such as inflammation and tau aggregation. Prior to this PPG proposal, we found that synaptic and network activity is tightly coupled with the release of the A? peptide in the extracellular space of the brain as part of a normal biological process. Our labs discovered some of the cellular mechanisms that link synaptic transmission and network activity with dynamic changes in A? levels in awake, behaving mice with confirmation in human studies. This collaborative work led to the submission and funding of the current PPG which has been funded from 4/1/12 to the present. We have made substantial progress over the last 4 years. Some key findings are that the sleep/wake cycle regulates A? levels dynamically with A? release being higher during wake and lower during sleep. This effect, at least in part, is via neuronal activity differences between wake and sleep. We also found that A? and tau release by neurons is controlled by synaptic activity and can be monitored dynamically. It was also found that A? levels, clearance, and aggregation can be strongly influenced by neuronal LRP1 and heparan sulfate proteoglycans (HSPG). In addition to our findings, increasing evidence indicates that once key proteins involved in neurodegenerative diseases aggregate in the brain (e.g. A? and tau), they appear to spread from one region to others within neuronal networks that are synaptically connected. There is also growing evidence that in AD, A? aggregation in some way drives the progression and spread of tauopathy. We believe that new studies are now warranted to understand the relationship between synaptic and network activity, the sleep/wake cycle, and the impact of the apoE/HSPG/LRP1 on A?, tau, and the spreading of these protein aggregates in the brain. The overall hypothesis of this PPG renewal is that the sleep-wake cycle and brain network activity modulates both A? and tau aggregation and the effect of A? on tau spreading. We further hypothesize that apoE/LRP1/HSPG pathways influence these effects. We will utilize innovative techniques and approaches to study these hypotheses such as the use of DREADDs, in vivo microdialysis, and microimmunoelectrodes as well as a variety of genetically modified mouse models and viral vectors. The specific projects and Cores are listed here. Project 1, D. Holtzman, PI: Effects of the sleep/wake cycle on A?, tau, and spreading. Project 2, J. Cirrito, PI: Neuronal Network Regulation in A? and Tau Conformation and Spreading. Project 3, G. Bu, PI: Neuronal LRP1 and HSPG in pathological spreading of A? and tau. Core A: Administration (D. Holtzman, PI); Core B: Viral Vectors Core (B. J. Snider, PI).